tbuckley/cabot-search huggingface dataset:
Abstract IA002: Contextual determinants of pancreatic tumorigenesis
Authors: Dafna Bar-Sagi
Journal: Cancer Research (2022)

Abstract Pancreatic cancer, in its most common form - pancreatic ductal (PDAC) - is one of the most lethal cancers with overall 5-year survival of 11%. Approximately 61,000 new cases of PDAC were diagnosed in the US in the past year, and the incidence is rising at a rate of 0.5% to 1.0% per year. On this trajectory, PDAC is projected to become the second most common cause of cancer-related deaths in the US. The evolution of PDAC is driven by a network of complex molecular and cellular alterations that affect the tumor cells themselves and the environment that surrounds them. The focus of our efforts has been to define the context-dependent contribution of these alterations to the pathophysiological characteristics of PDAC with the goal of leveraging this information to identify actionable vulnerabilities in this disease. Citation Format: Dafna Bar-Sagi. Contextual determinants of pancreatic tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA002.
Abstract A027: Validation of an early-stage pancreatic cancer classification model using 5-Hydroxymethylation profiles in plasma-derived cell-free DNA
Authors: Anna Bergamaschi, David Haan, Micah Collins, Gulfem Guler, Melissa Peters, Lauren Gigliotti, Shimul Chowdhury, Wayne Volkmuth, Samuel Levy
Journal: Cancer Research (2022)

Abstract Background: Pancreatic cancer outcomes are poor, mostly due to the detection of cancer at late stages. Early-detection enables prompt initiation of treatment and has been reported to significantly improve outcomes. We have developed a novel sequencing-based epigenomics technology for cancer early-detection that enriches 5-hydroxymethylcytosine (5hmC) loci in cell-free DNA (cfDNA), and via machine learning algorithms, enables the detection of pancreatic cancer. Method: Whole-blood was obtained from a training cohort of 660 individuals (consisting of 132 pancreatic cancers (PaCa) and 528 non-cancers) and a validation cohort of 593 individuals (consisting of 86 PaCa and 507 non-cancers). cfDNA was isolated from plasma and 5hmC and whole-genome libraries were sequenced. Logistic regression algorithms were employed using 5hmC feature sets combined with physical characteristics to optimally partition cancers from non-cancers. Results: We trained and cross-validated a binomial logistic-regression model on PaCa and non-cancer samples. Cross validation of the training model yielded an overall sensitivity of 65.9%, early-stage (stage I-II) sensitivity of 57.1% and a specificity of 98%. The model was further validated on an independent set and yielded an overall sensitivity of 64%, early-stage sensitivity of 64.7% and a specificity of 98%. Conclusion: Our results demonstrate that plasma-derived cfDNA 5hmC profiles enable the detection of PaCa in early-stage disease providing a valuable tool especially for those individuals at high risk. A larger clinical study (NODMED: NCT05188586) is underway to validate the test in a high-risk population that would most benefit from early-detection. Citation Format: Anna Bergamaschi, David Haan, Micah Collins, Gulfem Guler, Melissa Peters, Lauren Gigliotti, Shimul Chowdhury, Wayne Volkmuth, Samuel Levy. Validation of an early-stage pancreatic cancer classification model using 5-Hydroxymethylation profiles in plasma-derived cell-free DNA [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A027.
Abstract B059: RNA exosome component EXOSC4 amplified in multiple cancer types is required for the pancreatic cancer cell survival via the regulation of BIK and SESN2 mRNA
Authors: Kenzui Taniue, Yusuke Mizukami, Nobuyoshi Akimitsu
Journal: Cancer Research (2022)

Abstract RNA decay plays a crucial role in the post-transcriptional regulation of gene expression. The RNA exosome is a multi-subunit ribonuclease complex that is evolutionally conserved and the major cellular machinery for the surveillance, processing, degradation, and turnover of diverse RNAs essential for cell viability. The RNA exosome is composed of a catalytically inactive barrel structure of nine core subunits (known as EXO9) that achieves its catalytic activity via the interaction with the exoribonuclease exosome component 10 (EXOSC10), the exo/endo-ribonuclease DIS3, and the two DIS3-like proteins (the exoribonucleases DIS3L and DIS3L2). Moreover, exosome activity is regulated by associated co-factors and RNA-binding adaptor proteins that recruit the exosome to its many targets. Here we performed integrated genomic and clinicopathological analyses of 27 RNA exosome components across 32 tumor types using The Cancer Genome Atlas PanCancer Atlas Studies’ datasets. We discovered that the EXOSC4 gene, which encodes a barrel component of the RNA exosome, was amplified across multiple cancer types. We further found that EXOSC4 alteration is associated with a poor prognosis in pancreatic cancer patients. Moreover, we demonstrated that EXOSC4 is required for the survival of pancreatic cancer cells. EXOSC4 also repressed BIK expression and destabilized SESN2 mRNA by promoting its degradation. Furthermore, knockdown of BIK and SESN2 could partially rescue pancreatic cells from the reduction in cell viability caused by EXOSC4 knockdown. Our study provides evidence for EXOSC4-mediated regulation of BIK and SESN2 mRNA in the survival of pancreatic tumor cells. Citation Format: Kenzui Taniue, Yusuke Mizukami, Nobuyoshi Akimitsu. RNA exosome component EXOSC4 amplified in multiple cancer types is required for the pancreatic cancer cell survival via the regulation of BIK and SESN2 mRNA [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B059.
Abstract A041: Extracellular vesicle based ALPPL2 and THBS2 as biomarkers for monitoring disease burden in patients with pancreatic cancer
Authors: Kuntal Halder, Gayle Jameson, Erkut Borazanci, Amber Vrana, Derek Cridebring, Daniel Von Hoff, Haiyong Han
Journal: Cancer Research (2022)

Abstract Pancreatic cancer is a highly lethal disease that is often diagnosed at a late stage, when it has metastasized to other organs. Several therapeutic options have been shown to be effective at significantly shrinking the tumor and improving survival. Unfortunately, very few of these treatments lead to the total disappearance of tumor and therefore require changes to the treatment strategy. One of the challenges is rapidly identifying if a treatment works or when it stops working so patients can be switched to another regimen. Currently, the best blood-based marker for tracking disease burden in patients with pancreatic cancer is CA19-9. Unfortunately, 15-20% of pancreatic cancer patients do not have elevated levels of this marker with a disproportionate number of non-CA19-9 elevated cases being African American and Hispanic patients. In addition, changes in this marker do not always correlate with disease burden since there are other factors that can change CA19-9 levels. In this study, we have identified two blood extracellular vesicle (EV) based protein markers THBS2 (Thrombospondin 2) and ALPPL2 (Alkaline phosphatase, placental-like 2) that aid in monitoring pancreatic cancer disease burden in both CA19-9 secretors and non-secretors. We found that the number of THBS2+ or ALPPL2+ EVs was significantly higher in serum samples from patients with pancreatic cancer than those from healthy controls. The level of THBS2+ or ALPPL2+ EVs in patients with pancreatic cancer correlated with a patient's response to treatment. In patients who have elevated CA19-9, the level of THBS2+ or ALPPL2+ EVs correlates with the changes in CA19-9 upon treatment. In CA19-9 negative patients, the level of THBS2+ EVs or ALPPL2+ EVs correlates with the tumor size changes (RECIST response) upon treatment. Hence, EVs containing THBS2 or ALPPL2 can potentially serve as additional and more informative biomarkers for monitoring disease burden in patients with pancreatic cancer regardless of their CA19-9 status. This work was supported by the Flinn Foundation and the HonorHealth Research Institute). Citation Format: Kuntal Halder, Gayle Jameson, Erkut Borazanci, Amber Vrana, Derek Cridebring, Daniel Von Hoff, Haiyong Han. Extracellular vesicle based ALPPL2 and THBS2 as biomarkers for monitoring disease burden in patients with pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A041.
Abstract B003: Pancreatic cancer cells activate arginine biosynthesis to adapt to myeloid-driven amino acid stress in the tumor microenvironment
Authors: Juan J. Apiz Saab, Lindsey N. Dzierozynski, Patrick B. Jonker, Zhou Zhu, Riona N. Chen, Moses Oh, Colin Sheehan, Kay F. Macleod, Christopher R. Weber, Alexander Muir
Journal: Cancer Research (2022)

Abstract Nutrient stress in the tumor microenvironment requires cancer cells to adopt adaptive metabolic programs to maintain survival and proliferation. Therefore, knowledge of microenvironmental nutrient levels and how cancer cells cope with such nutrition is critical to understand the metabolism underpinning cancer cell biology. Previously, we performed quantitative metabolomics of the interstitial fluid (the local perfusate) of pancreatic ductal adenocarcinoma (PDAC) tumors to comprehensively characterize nutrient availability in the microenvironment of these tumors. We have used this information to develop Tumor Interstitial Fluid Medium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling study of PDAC metabolism under physiological nutrition. By transcriptomic analysis, we show that PDAC cells cultured in TIFM, compared to standard culture models, adopt a cellular state more similar to PDAC cells in tumors. Using the TIFM model, we then identified arginine biosynthesis as a critical metabolic adaptation PDAC cells engage to cope with microenvironmental nutrition. We further find that arginine biosynthesis enables PDAC cells to cope with microenvironmental arginine starvation, which we show is driven by myeloid cells in PDAC tumors. Altogether, these data show that nutrient availability in the microenvironment is an important determinant of PDAC metabolism and behavior, and models incorporating tumor nutrition enable detailed and mechanistic study of microenvironmentally-programmed PDAC cell states and phenotypes. Further, through use of the TIFM model, we identified both myeloid-driven arginine starvation as a major metabolic stress prevalent in the PDAC microenvironment, and the metabolic adaptations PDAC cells use to counter this nutritional challenge. Citation Format: Juan J. Apiz Saab, Lindsey N. Dzierozynski, Patrick B. Jonker, Zhou Zhu, Riona N. Chen, Moses Oh, Colin Sheehan, Kay F. Macleod, Christopher R. Weber, Alexander Muir. Pancreatic cancer cells activate arginine biosynthesis to adapt to myeloid-driven amino acid stress in the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B003.
Novel variants in <i>GALE</i> cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis
Authors: Ana Marín-Quílez, Christian Andrea Di Buduo, Lorena Díaz-Ajenjo, Vittorio Abbonante, Elena Vuelta, Paolo Maria Soprano, Cristina Miguel-García, Sandra Santos-Mínguez, Inmaculada Serramito-Gómez, Pedro Ruiz-Sala, María Jesús Peñarrubia, Emilia Pardal, Jesús María Hernández-Rivas, José Ramón González-Porras, Ignacio García-Tuñón, Rocío Benito, José Rivera, Alessandra Balduini, José María Bastida
Journal: Blood (2022)

Abstract Glycosylation is recognized as a key process for proper megakaryopoiesis and platelet formation. The enzyme uridine diphosphate (UDP)-galactose-4-epimerase, encoded by GALE, is involved in galactose metabolism and protein glycosylation. Here, we studied 3 patients from 2 unrelated families who showed lifelong severe thrombocytopenia, bleeding diathesis, mental retardation, mitral valve prolapse, and jaundice. Whole-exome sequencing revealed 4 variants that affect GALE, 3 of those previously unreported (Pedigree A, p.Lys78ValfsX32 and p.Thr150Met; Pedigree B, p.Val128Met; and p.Leu223Pro). Platelet phenotype analysis showed giant and/or grey platelets, impaired platelet aggregation, and severely reduced alpha and dense granule secretion. Enzymatic activity of the UDP-galactose-4-epimerase enzyme was severely decreased in all patients. Immunoblotting of platelet lysates revealed reduced GALE protein levels, a significant decrease in N-acetyl-lactosamine (LacNAc), showing a hypoglycosylation pattern, reduced surface expression of gylcoprotein Ibα-IX-V (GPIbα-IX-V) complex and mature β1 integrin, and increased apoptosis. In vitro studies performed with patients-derived megakaryocytes showed normal ploidy and maturation but decreased proplatelet formation because of the impaired glycosylation of the GPIbα and β1 integrin, and reduced externalization to megakaryocyte and platelet membranes. Altered distribution of filamin A and actin and delocalization of the von Willebrand factor were also shown. Overall, this study expands our knowledge of GALE-related thrombocytopenia and emphasizes the critical role of GALE in the physiological glycosylation of key proteins involved in platelet production and function.
Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial
Authors: Peter Hillmen, Barbara Eichhorst, Jennifer R. Brown, Nicole Lamanna, Susan M. O'Brien, Constantine S. Tam, Lugui Qiu, Maciej Kazmierczak, Keshu Zhou, Martin Šimkovič, Jiří Mayer, Amanda Gillespie-Twardy, Mazyar Shadman, Alessandra Ferrajoli, Peter S. Ganly, Robert Weinkove, Sebastian Grosicki, Andrzej Mital, Tadeusz Robak, Anders Österborg, Habte A. Yimer, Tommi Salmi, Meng Ji, Jessica Yecies, Adam Idoine, Kenneth Wu, Jane Huang, Wojciech Jurczak
Journal: Journal of Clinical Oncology (2022)

Zanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition. We hypothesized that complete/sustained BTK occupancy may improve efficacy outcomes and increased BTK specificity may minimize off-target inhibition-related toxicities.ALPINE (ClinicalTrials.gov identifier: NCT03734016) is a global, randomized, open-label phase III study of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia. The primary end point was investigator-assessed overall response rate (ORR). The preplanned interim analysis was scheduled approximately 12 months after the first 415 patients were enrolled.Between November 1, 2018, and December 14, 2020, 652 patients were enrolled. We present the interim analysis of the first 415 enrolled patients randomly assigned to receive zanubrutinib (n = 207) or ibrutinib (n = 208). At 15 months of median follow-up, ORR (partial or complete response) was significantly higher with zanubrutinib (78.3%; 95% CI, 72.0 to 83.7) versus ibrutinib (62.5%; 95% CI, 55.5 to 69.1; two-sided P < .001). ORR was higher with zanubrutinib versus ibrutinib in subgroups with del(17p)/TP53 mutations (80.5% v 50.0%) and del(11q) (83.6% v 69.1%); 12-month progression-free survival in all patients was higher with zanubrutinib (94.9%) versus ibrutinib (84.0%; hazard ratio, 0.40; 95% CI, 0.23 to 0.69). Atrial fibrillation rate was significantly lower with zanubrutinib versus ibrutinib (2.5% v 10.1%; two-sided P = .001). Rates of cardiac events, major hemorrhages, and adverse events leading to treatment discontinuation/death were lower with zanubrutinib.Zanubrutinib had a significantly higher ORR, lower atrial fibrillation rate, and improved progression-free survival and overall cardiac safety profile versus ibrutinib. These data support improved efficacy/safety outcomes with selective BTK inhibition.
Safety and efficacy of propranolol for treatment of familial cerebral cavernous malformations (Treat_CCM): a randomised, open-label, blinded-endpoint, phase 2 pilot trial
Authors: Silvia Lanfranconi, Elisa Scola, Jennifer M T A Meessen, Roberto Pallini, Giulio A Bertani, Rustam Al-Shahi Salman, Elisabetta Dejana, Roberto Latini, Giorgia Abete Fornara, Nicolò M. Agnelli, Alessio Albanese, Issam Awad, Renzo Bagnati, Giovanna Balconi, Elena Ballabio, Ettore Beghi, Roberto Bernasconi, Giulio A. Bertani, Silvia Besana, Adriana Blanda, Chiara Bossi, Nereo Bresolin, Maria G. Buratti, Roberta Calabrese, Maria R. Carriero, Marco Castori, Elisa F. Ciceri, Rossella Ciurleo, Giacomo P. Comi, Valeria Contarino, Giorgio Conte, Leonardo D'Agruma, Giorgio Q. D'Alessandris, Ugo de Grazia, Rina Di Bonaventura, Piergiorgio d'Orio, Giuseppe Farago', Andreana Foresta, Carmela Fusco, Chiara Gaudino, Maria G. Lampugnani, Alessia Lanno, Francesca Lazzaroni, Cornelia Lee, Marco Locatelli, Aldo P. Maggioni, Peetra Magnusson, Matteo Malinverno, Maurizio Mangiavacchi, Antonella Mangraviti, Silvia Marino, Selene Mazzola, Enrico B. Nicolis, Deborah Novelli, Maria L. Ojeda Fernandez, Antonio Petracca, Fabrizio Pignotti, Simona Pogliani, Marco Poloni, Alessandro Prelle, Pamela Raggi, Franca Raucci, Caroline Regna-Gladin, Dario Ronchi, Emma Scelzo, Salim Seyfried, Anna Simeone, Carmelo L. Sturiale, Laura Tassi, Mauro Tettamanti, Valter Torri, Elisabeth Tournier-Lasserve, Rita Treglia, Fabio M. Triulzi, Celeste Ungaro, Elison Ursi, Gloria Valcamonica, Antonella Vasami', Barbara Zarino
Journal: The Lancet Neurology (2022)
Primary Thyroid Mucoepidermoid Carcinoma (MEC) Is Clinically, Prognostically, and Molecularly Different from Sclerosing MEC with Eosinophilia: A Multicenter and Integrated Study
Authors: Hieu Trong Le, Truong P. X. Nguyen, Mitsuyoshi Hirokawa, Ryohei Katoh, Norisato Mitsutake, Michiko Matsuse, Ayaka Sako, Tetsuo Kondo, Nilesh Vasan, Young Mi Kim, Ying Liu, Lewis Hassell, Kennichi Kakudo, Huy Gia Vuong
Journal: Endocrine Pathology (2022)
Ribosome stalling is a signal for metabolic regulation by the ribotoxic stress response
Authors: Goda Snieckute, Aitana Victoria Genzor, Anna Constance Vind, Laura Ryder, Mark Stoneley, Sébastien Chamois, René Dreos, Cathrine Nordgaard, Frederike Sass, Melanie Blasius, Aida Rodríguez López, Sólveig Hlín Brynjólfsdóttir, Kasper Langebjerg Andersen, Anne E. Willis, Lisa B. Frankel, Steen Seier Poulsen, David Gatfield, Zachary Gerhart-Hines, Christoffer Clemmensen, Simon Bekker-Jensen
Journal: Cell Metabolism (2022)

Impairment of translation can lead to collisions of ribosomes, which constitute an activation platform for several ribosomal stress-surveillance pathways. Among these is the ribotoxic stress response (RSR), where ribosomal sensing by the MAP3K ZAKα leads to activation of p38 and JNK kinases. Despite these insights, the physiological ramifications of ribosomal impairment and downstream RSR signaling remain elusive. Here, we show that stalling of ribosomes is sufficient to activate ZAKα. In response to amino acid deprivation and full nutrient starvation, RSR impacts on the ensuing metabolic responses in cells, nematodes, and mice. The RSR-regulated responses in these model systems include regulation of AMPK and mTOR signaling, survival under starvation conditions, stress hormone production, and regulation of blood sugar control. In addition, ZAK-/- male mice present a lean phenotype. Our work highlights impaired ribosomes as metabolic signals and demonstrates a role for RSR signaling in metabolic regulation.
MlrA, a MerR family regulator in <i>Vibrio cholerae</i> , senses the anaerobic signal in the small intestine of the host to promote bacterial intestinal colonization
Authors: Jialin Wu, Yutao Liu, Wendi Li, Fan Li, Ruiying Liu, Hao Sun, Jingliang Qin, Xiaohui Feng, Di Huang, Bin Liu
Journal: Gut Microbes (2022)

Vibrio cholerae (V. cholerae), one of the most important bacterial pathogens in history, is a gram-negative motile bacterium that causes fatal pandemic disease in humans via oral ingestion of contaminated water or food. This process involves the coordinated actions of numerous regulatory factors. The MerR family regulators, which are widespread in prokaryotes, have been reported to be associated with pathogenicity. However, the role of the MerR family regulators in V. cholerae virulence remains unknown. Our study systematically investigated the influence of MerR family regulators on intestinal colonization of V. cholerae within the host. Among the five MerR family regulators, MlrA was found to significantly promote the colonization capacity of V. cholerae in infant mice. Furthermore, we revealed that MlrA increases bacterial intestinal colonization by directly enhancing the expression of tcpA, which encodes one of the most important virulence factors in V. cholerae, by binding to its promoter region. In addition, we revealed that during infection, mlrA is activated by anaerobic signals in the small intestine of the host through Fnr. In summary, our findings reveal a MlrA-mediated virulence regulation pathway that enables V. cholerae to sense environmental signals at the infection site to precisely activate virulence gene expression, thus providing useful insights into the pathogenic mechanisms of V. cholerae.
Preclinical efficacy of azacitidine and venetoclax for infant KMT2A-rearranged acute lymphoblastic leukemia reveals a new therapeutic strategy
Authors: Laurence C. Cheung, Carlos Aya-Bonilla, Mark N. Cruickshank, Sung K. Chiu, Vincent Kuek, Denise Anderson, Grace-Alyssa Chua, Sajla Singh, Joyce Oommen, Emanuela Ferrari, Anastasia M. Hughes, Jette Ford, Elena Kunold, Maria C. Hesselman, Frederik Post, Kelly E. Faulk, Erin H. Breese, Erin M. Guest, Patrick A. Brown, Mignon L. Loh, Richard B. Lock, Ursula R. Kees, Rozbeh Jafari, Sébastien Malinge, Rishi S. Kotecha
Journal: Leukemia (2022)

Abstract Infants with KMT2A -rearranged B-cell acute lymphoblastic leukemia (ALL) have a dismal prognosis. Survival outcomes have remained static in recent decades despite treatment intensification and novel therapies are urgently required. KMT2A -rearranged infant ALL cells are characterized by an abundance of promoter hypermethylation and exhibit high BCL-2 expression, highlighting potential for therapeutic targeting. Here, we show that hypomethylating agents exhibit in vitro additivity when combined with most conventional chemotherapeutic agents. However, in a subset of samples an antagonistic effect was seen between several agents. This was most evident when hypomethylating agents were combined with methotrexate, with upregulation of ATP-binding cassette transporters identified as a potential mechanism. Single agent treatment with azacitidine and decitabine significantly prolonged in vivo survival in KMT2A -rearranged infant ALL xenografts. Treatment of KMT2A -rearranged infant ALL cell lines with azacitidine and decitabine led to differential genome-wide DNA methylation, changes in gene expression and thermal proteome profiling revealed the target protein-binding landscape of these agents. The selective BCL-2 inhibitor, venetoclax, exhibited in vitro additivity in combination with hypomethylating or conventional chemotherapeutic agents. The addition of venetoclax to azacitidine resulted in a significant in vivo survival advantage indicating the therapeutic potential of this combination to improve outcome for infants with KMT2A -rearranged ALL.